There has been extensive research in the area of biodegradable matrices for controlled release of drugs. Biodegradable matrices for drug delivery are useful because they obviate the need for additional medical intervention for removal of non-degradable drug depleted devices. The ideal polymeric formulation for delivering drug in a controlled manner must possess a variety of attributes. The polymer should be compatible with biological tissues and should also be biodegradable, having degradation components that are non-toxic and easily eliminated. The polymer should be hydrophobic so that it maintains its integrity in physiological environments, and should have versatile and predictable degradation and drug release profiles for both hydrophilic and/or hydrophobic agents. Generally, the polymer should be in a liquid or gel form at room temperature to facilitate administration to a target delivery site in a patient, but should increase in viscosity after administration so that the polymer is not dislodged or dispersed from the delivery site. A preferred polymer should be stable under normal storage conditions over extended periods of time. Finally, a preferred polymer should be easy to prepare at low cost without the need for expensive reagents or apparatus.
Many biodegradable polymers have been evaluated for use as implantable controlled drug release matrices, including polyesters, polycarbonates, natural and synthetic polyamides, polyphosphate esters, polyphosphazenes and polyanhydrides.
While hundreds of different polyanhydride polymers have been reported, not many may be considered to be practical carriers for drugs. First, many are composed of synthetic aromatic or heterocyclic monomers, which present the risk of toxicity and slow elimination rate after degradation. Second, these polymers tend to be highly sensitive to heat and moisture, which makes them unstable even at 0-5° C., necessitating storage at −20° C. or below. Thus, it can be challenging to deliver products containing these polymers to hospitals and other end-users. One polyanhydride device in clinical use is the GLIADEL® brain implant, which is manufactured by Guilford Pharmaceuticals. This product requires constant storage at −20° C. because at higher temperatures, the material degrades, with the molecular weight of the polymer carrier dropping from 20,000-110,000 to below 20,000 Daltons, deleteriously affecting the drug release rate and also contributing to the rejection of the device. Many polyanhydrides are composed of linear aliphatic acids, making them both crystalline and fragile. Such compositions are impractical as they may fragment during shipment or use. Furthermore, the crystalline (or otherwise solid) matrices must be inserted into a patient using surgical techniques, rather than by less invasive injection or laparoscopic procedures.
Poly(ester-anhydrides) formed from ricinoleic acid and natural fatty diacids have been disclosed in U.S. Pat. Nos. 7,297,347 and 7,749,539 to Domb. These polymers may be admixed with a variety of bioactive agents including small drug molecules, peptides and proteins. The drug delivery compositions are administered to a patient in a liquid, gel or paste form and are able to release the incorporated bioactive agent over several weeks. Although the poly(ester-anhydrides) represent a significant advance in the field of biodegradable polymer matrices, several key issues remain to be overcome to obtain a robust, clinically useful material.
The hitherto known poly(ester-anhydrides) are composed of a random sequence of ricinoleic acid and fatty diacids, and as such, do not exhibit consistent stability and other properties over the bulk of the material and may also exhibit significant batch to batch variability. Unlike other fatty acids, which are monofunctional, ricinoleic acid is a bifunctional fatty acid with one hydroxyl group along its chain. This bifunctionality allows the incorporation of ricinoleic acid units into fatty diacids, such as a polysebacic acid (PSA) framework. The lipophilic side chains of ricinoleic acid increase lipophilicity, and also hinder hydrolytic degradation. Accordingly, the rate of hydrolysis of this poly(ester-anhydride) polymer can be appropriately controlled by the amount of ricinoleic acid units incorporated in the framework. However, if ricinoleic acid is incorporated into the polymer in a random sequence using the hitherto known synthetic methods, the thus obtained polymer may exhibit undesirable characteristics. For example, the polymer may exhibit increased sensitivity to hydrolysis and depolymerization, thereby contributing to the overall instability of the polymer.
In addition, improper or inadequate reaction conditions during synthesis may result in the formation of short polymer chains and oligomeric impurities. The short polymer chains tend to affect the rigidity and viscosity of the entire composition thereby leading to irreproducible physical and chemical characteristics of the obtained polymer.
There remains a strong need for stable liquid or gel polymeric formulations that can be administered into the tissue with versatility in polymer degradation and drug release profile. There further remains a need for a facile and robust method of preparing poly(ester-anhydride) copolymers suitable as carriers for drug delivery.